The present invention relates in general to thrombolysis of coronary artery blood clots, and in particular to achieving rapid lysis of coronary thromboses by means of transthoracic unsound.
It is known that coronary artery thrombosis is a leading cause of morbidity and mortality in the western world today. In this condition, a blood clot forms in a coronary artery, resulting in absent or inadequate blood flow to part of the heart muscle (myocardium). If adequate blood supply to the myocardium is not reestablished within minutes of onset of the thrombosis, the myocardiurn undergoes ischenmia (cell damage), and later infarction (cell death). Effective treatment of coronary thrombosis thus depends on achieving dissolution of the thrombus (thrombolysis) as soon as possible after the onset of symptoms, and this is most commonly achieved by intravenous adminiration of a thrombolytic agent, such as tissue plasminogen activator (tpA).
Once a coronary thrombosis has been diagnosed, early thrombolysis is initiated as soon as possible. Ideally, this is done by medical or paramedical personnel at the point at which they first encounter the patient. Thus an ambulance team may initiate early thrombolysis prior to transporting a patient to the hospital or hospital staff may initiate thrombolysis immediately upon arrival of a patient in the Emergency Room.
As the rapidity with which coronary blood flow is reestablished determines the long-term prognosis for the patient, there has been much interest in finding ways of augmenting or replacing standard early thrombolytic treatment protocols so as to achieve more rapid or more effective thrombolysis. For an early thrombolytic technique to be clinically useful, however, it is necessary that the technique be easily administered by the first medical personnel to encounter the patient (often an ambulance team or Emergency Room staff), at the point at which they first encounter the patient (often in the patient""s home or in the hospital Emergency Room), over a short period of time.
It is known that application of ultrasound energy to organic tissue can result in disruption of the tissue, if the intensity of the ultrasound energy focused on the tissue is high enough Thus, ultrasonic lithotripsy has become a standard method for treating renal stones, whereby ultrasound energy focused on a renal stone causes the stone to disintegrate. Blood clots, too, have been shown to undergo thrombolysis when exposed to high intensity ultrasonic energy, and this technique has been successfully used to achieve thrombolysis both in-vitro and in-vivo.
Despite the proven efficacy of ultrasound as a method for achieving thrombolysis, clinical application of this modality in the early treatment of coronary artery thrombosis has been inhibited by the technical difficulties involved in delivering effective amounts of ultrasound energy to coronary arteries, which are both small in diameter (measuring only a few millimeters) and highly mobile (due to the constant contraction and relaxation of the myocardium in which the arteries lie). Due to the mobility and small size of coronary thrombi, it has not been possible, to date, to reliably focus transthoracic ultrasound energy on a coronary thrombosis, as the focal point changes from second to second with the beating of the heart.
Real time ultrasonic localization of blood clots has been reported by Unger et al (The Use of a Thrombus-Specific Ultrasound Contrast Agent to Detect Thrombus in Arteriovenous Fistulae Investigative Radiology; volume 35; number 1: 86-89), who showed that injection of a thrombus-specific ultrasound contrast agent facilitated the ultrasonic diagnosis of clots in AV fistulae. In Unger""s report, large amounts of contrast agent adhered to static clots, thus enabling the increased echogenicity of the clots to be appreciated on ultrasound imaging. This technique, however, does not work for thromboses in the small, low flow, coronary arteries, in which only small amounts of contrast agent adhere to the thrombi. Rosenscheim et al (Ultrasound Image Guided Noninvasive Ultrasound Thrombolysis, Circulation 2000;102:238-245) have described a method for ultrasonic diagnosis of peripheral blood clots combined with immediate ultrasound thrombolysis of the detected clots. Their technique for thrombolysis, however, is slow (taking several minutes), thus precluding it""s use in coronary thrombi which change location with the beating of the heart every few seconds.
It should be noted that both of the above described methods for ultrasonic diagnosis and localization of vascular thrombi employ standard ultrasonic imaging techniques, whereby the amplitudes of reflected ultrasound waves are analyzed so as to construct an image of the thrombus. In terms of standard ultrasound imaging techniques, therefore, only objects which produce reflected ultrasound signals of sufficiently high amplitude as to allow the signals to be individually detected by the receiving ultrasound crystal can be imaged.
To date, several techniques for achieving coronary ultrasound thrombolysis have been described:
1. Administration of the ultrasound by means of an intravascular ultrasound (IVUS) transducer. In this technique, a small ultrasound transducer located on the tip of a coronary artery catheter is advanced through the coronary circulation and positioned on the thrombus. Ultrasound energy is then administered directly onto the clot, allowing a sufficient intensity of ultrasound energy to be achieved in the thrombus as to cause disruption of the blood clot. As the catheter in the artery moves along with the pulsations of the myocardium, unnecessary exposure of surrounding tissue to damaging ultrasound energy is minimized. Several authors have reported. the clinical use of intravascular ultrasound to achieve coronary thrombolysis. IVUS, however, suffers from the deficiency that it entails cardiac catheterization in a catheterization laboratory. It is thus very invasive and time consuming, and cannot be performed within minutes of the onset of symptoms in a patient suffering from a coronary thrombosis.
2. Administration of ultrasound to the entire thorax (Siegel et al: Noninvasive. Transthoracic, Low-Frequency Ultrasound Augments Thrombolysis in a Canine Model of Acute Myocardial Infarcation Circulation. 2000;101:2026). In this technique as coronary angiography or IVUS are not performed, the exact spatial location of the coronary thrombosis is not known, and the entire thorax is exposed to ultrasound energy. So as to achieve a sufficient intensity of ultrasound energy in the blood clot, very high levels of ultrasound energy have to be used. This technique suffers from the deficiency that the ultrasound energy is not focused on the thrombus. Healthy tissue is thereby exposed to damaging levels of ultrasound energy. In addition, as the amount of ultrasound energy actually reaching the thrombus is small, very long treatment times (up to ninety minutes) are required to achieve thrombolysis. This technique is thus impractical and dangerous for use in humans, and not clinically useful as a method of early coronary thrombolysis.
3. Augmentation of extrathoracically applied ultrasound energy by an intravenous ultrasound contrast agent. (Wu Y et al: Binding and lysing of blood clots using X-408. Invest Radiol 1998:33: 880-885). In this technique, an ultrasound contrast agent such as MRX408 is administered intravenously, prior to the application of ultrasound energy to the entire thorax. It is known that ultrasound contrast agents may enhance the absorption of specific frequencies of ultrasound energy by the tissue to which the contrast agent is adhered. Administration of a contrast agent that specifically adheres to thrombi therefore decreases the amount of ultrasound energy that has to be administered extrathoracically so as to achieve an effective intensity of ultrasound energy in the clot. Although this technique entails lower exposure of healthy tissue to ultrasound energy than the technique of Siegel described above, this technique still suffers from the deficiency that up to thirty minutes of low energy ultrasound application is required to achieve thrombolysis. Shorter application times (five minutes) require the administration of dangerously high levels of ultrasound energy (420 kPa). This technique is thus too time consuming to be clinically useful as a method of early coronary thrombolysis.
Current techniques for achieving ultrasound thrombolysis of coronary blood clots are thus either laborious (requiring the performance of formal cardiac catheterization in a laboratory), time consuming (requiring at least 30 minutes of ultrasound exposure) or dangerous (due to excessive exposure of healthy tissue to damaging, unfocused, ultrasound energy). Thus, despite the efficacy of ultrasound as a modality for achieving thrombolysis, no currently known technique of ultrasound administration is clinically useful in the early treatment of coronary thrombosis.
There is therefore a need for, and it would be highly advantageous to have, a method for achieving ultrasonic coronary thrombolysis, which is rapid, portable and safe.
The present invention provides a method and apparatus for achieving thrombolysis of coronary artery thromboses by means of ultrasound energy. In terms of the present invention, a thrombus-specific ultrasound contrast agent is injected intravenously in a patient suspected of having a coronary thrombosis. An array of ultrasound transducers positioned on the patient""s chest then transmit ultrasound signals into the patient""s thorax, and receive the reflected echoes. Frequency or other temporal characteristics of the received echoes are analyzed by a computer processor in real time, so as to instantly identify and spatially localize coronary artery thromboses. Immediately upon identification and localization of a thrombus, ultrasound signals of sufficient energy to cause thrombolysis are transmitted into the thorax by the transducers, focused on the identified spatial location of the thrombus. The novelty of the present invention lies in the utilization only of frequency or other temporal characteristics of ultrasonic signals reflected off of coronary thrombi (as opposed to amplitude characteristics, as are utilized in all standard ultrasound imaging modalities) to localize the thrombi. In particular, the specific frequency characteristic utilized is the ratio, in the received signal, between the second and first harmonics of the ultrasound signal, where the first harmonic is the central frequency in which most of the energy had been transmitted.
Due to the small size of coronary artery thromboses, the amplitude of echoes reflected of off such thromboses is small, making it difficult to differentiate such echoes from background noise and achieve reliable two-dimensional imaging of coronary thromboses, using standard imaging techniques, even in the presence of an ultrasound contrast agent bound to the thrombus.
In addition to being generated by contrast bubbles, it is well known in the art that second harmonic components in reflected signals are also generated by native tissue, even in the absence of contrast bubbles. This native harmonic component is a disturbing factor when it is desired to detect contrast bubbles by utilizing the second harmonic component of a reflected signal, as in the case when bubbles are adherent to a coronary thrombus. A second harmonic component is also parasitically present in transmitted signals. This component, too, is a disturbing factor when it is desired to detect contrast bubbles by utilizing the second harmonic component of a reflected signal. To achieve optimal detection of second harmonic components of bubble origin, therefore, it is desirable to eliminate all signals which may originate in the native tissue, or which may parasitically be present in the transmitted signal.
The second harmonic content in the transmitted signal can be significantly reduced by appropriate tailoring of the envelop of the pulse, utilizing the technique of xe2x80x9cwindowingxe2x80x9d, by which the transmitted signal is multiplied in time by a xe2x80x98windowxe2x80x99 (e.g. a Gaussian function) so as to minimize second harmonics of the transmitted frequency, in a manner known also as apodization. The second harmonic component generated by the tissue can be significantly reduced by utilizing the technique of xe2x80x9ctissue native harmonic imaging.xe2x80x9d This technique is presently used in modern ultrasonic systems to improve sensitivity, and utilizes the amplitude characteristics of the received second harmonic signals to achieve two-dimensional imaging of organs, and the thrombus within. However, as tissue non-linearity results in the generation of harmonics (in the reflected signal) originating from both native tissue and contrast bubbles, amplitude-based imaging of these signals may still be inadequate to differentiate a small thrombus from surrounding native tissue.
The present invention is based on the observation that contrast bubbles exhibit a type of non-linearity which is different to that exhibited by native tissue. Typical bubble non-linearity in ultrasound reflection results in the generation of a second harmonic component which is relatively greater than that generated by native tissue, while the first harmonic components caused by bubble and native tissue non-linearity are relatively similar. Thus the ratio between the second and first transmitted harmonics of reflected echoes is notably higher for signals reflected off of a thrombus-specific ultrasound contrast agent than for signals reflected off of native organic tissues. Detection of a high ratio between the second and first transmitted harmonics thus indicates the presence of a thrombus in the ultrasonic field of interrogation Determination of this ratio can be achieved instantaneously by a standard computer processor receiving data input from the transducer array, without the need for actual amplitude-based visualization of the tissue under interrogation. Furthermore, as the array is comprised of several transducers at different locations to each other on the thorax, the spatial source of the reflected signal having a high second to first harmonic ratio can be geometrically calculated by the processor. As the calculations required to achieve diagnosis and localization of a thrombus by his method can be performed automatically and instantaneously, and as thrombolysis by means of the same transducer array can be initiated automatically by the computer processor (before the coronary artery has had time to move because of myocardial contraction), the method of the present invention allows for the rapid diagnosis and ultrasonic thrombolysis of coronary artery thromboses.
According to the teachings of the present invention, therefore, there is provided a method for diagnosing a thrombus, including introducing an ultrasound contrast agent into a human body, transmitting an ultrasound signal into the human body at at least one transmission frequency, receiving an ultrasound signal from the human body, quantifying a first temporal characteristic and a second temporal characteristic of the received ultrasound signal, describing a relationship between the first and second temporal characteristics, and inferring a diagnosis of a thrombus from the described relationship. There is farther provided a method for localizing a thrombus in a human body, including introducing an ultrasound contrast agent into the human body, transmitting an ultrasound signal towards the thrombus at at least one transmission frequency, receiving, at a plurality of locations, a plurality of ultrasound signals reflected off of the thrombus, each of the received ultrasound signals having an increased ratio of a first temporal characteristic to a second temporal characteristic, quantifying a time-of-flight for each of the received ultrasound signals, and calculating a spatial location of the thrombus from the time-of-flight quantities. There is further provided a method for lysing a thrombus in a human body, including introducing an ultrasound contrast agent into the human body, transmitting an ultrasound signal towards the thrombus at at least one transmission frequency, receiving an ultrasound signal reflected off of the thrombus, the received ultrasound signal having a temporal characteristic, calculating a spatial location of the thrombus from the temporal characteristic, and transmitting ultrasound energy towards the spatial location There is further provided an apparatus for treating a thrombus in a human body, including a sheet of material, the sheet being placeable on the human body, a plurality of ultrasound transmitters for transmitting ultrasound signals into the human body, the transmitters being fixedly located within the sheet, and the transmitters being oriented within the sheet such that the transmission is effected into the human body, a plurality of ultrasound receivers for receiving ultrasound signals reflected from the human body, the receivers being fixedly located within the sheet, and the receivers being oriented within the sheet such that the reception is effected from the human body, a layer of ultrasound coupling medium applied to a surface of the ultrasound transmitters and the ultrasound receivers, the layer being conformable to a contour of the human body, and a processor for processing the received signals, the processor being functional to calculate a temporal characteristic of the received signals, and diagnose a thrombus from the calculated temporal characteristic.